Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful?

Maisel NC, Blodgett JC, Wilbourne PL, Humphreys K, Finney JW

CRD summary

The authors concluded that naltrexone should be considered for patients who have a goal of reducing heavy drinking days whereas acamprosate was a better option for those who seek abstinence. Given the limitations of the evidence it is not possible to determine which treatment is most effective under what circumstances. The authors’ conclusions may not be reliable.

Authors' objectives

To assess when naltrexone and acamprosate are most efficacious for treating alcohol use disorder.

Searching

PubMed, EMBASE and PsycINFO were searched for articles in English published between 1970 and 2009. Search terms were reported. Reference lists of included articles and relevant reviews were searched manually.

Study selection

Eligible studies were randomised placebo-controlled trials that assessed the efficacy of naltrexone or acamprosate for treatment of adults (aged at least 18 years) with alcohol misuse/alcohol use disorder. Eligible trials had to include at least five participants in each treatment group and assess at least one drinking outcome. Trials that focused on alcohol withdrawal, alcohol detoxification, alcohol challenges and so on were excluded. Trials of participants in an in-patient setting for the entire treatment and follow-up period were excluded.

Included trials were published between 1985 and 2009 and were in various countries; two trials were conducted in the UK. Trials compared naltrexone and/or acamprosate to placebo. Trial length ranged from 20 to 365 days. Most trials administered naltrexone at 50mg or 100mg or more per day. Acamprosate was administered as 1,998mg or approximately 3,000mg per day, or dosage by weight. Outcomes of interest were abstinence rate, percentage of days abstinent and time to first drink/relapse.

Some trials required participants to be abstinent or to receive detoxification treatment prior to treatment. It appeared that some trials included participants with comorbid cocaine dependency or psychiatric disorders. Some trials included concurrent psychosocial treatment.

The authors did not state how many reviewers screened studies for inclusion.

Assessment of study quality

The authors did not state that they assessed trial quality.

Data extraction

Dichotomous data were extracted to calculate odds ratios and continuous data were extracted or calculated to estimate standardised mean differences (using Cohen’s d). An aggregate measure of abstinence outcomes was calculated. Similar data were extracted and calculated for "heavy drinking" and/or craving.

A random-effects model was used to calculate overall effect sizes (Hedges’ g correction for small sample bias) and their 95% confidence intervals separately for naltrexone and acamprosate. An effect size of 0.2 was considered small, 0.5 was considered medium and 0.8 large.

Statistical heterogeneity was assessed using Cochrane Q and I² statistics; heterogeneity was evident where I² was at least low-to-moderate (approximately 35%) and the Q-statistic was significant.

Univariate mixed-effects methods were used to explore categorical moderators and maximum likelihood methods were used to explore continuous moderators and for meta-regression including all of the moderators (as stated in the paper). Correlations (r) were calculated to assess the interrelationships between moderators.

Sensitivity analyses were also performed (fully reported in the review).

The difference between the two treatments for aggregate heaving drinking outcomes was not statistically significant (p=0.16). Naltrexone showed a statistically significant improvement compared to placebo (g=0.19, 95% CI 0.12 to 0.25; I²=38.2%; 39 trials) and acamprosate did not (I²=32.5%; five trials).

Meta-regression including all of the moderators identified that for the effects of naltrexone versus placebo, only length of abstinence before treatment was a significant moderator for abstinence outcomes. Length of abstinence before treatment and "other" as the treatment goal were significant moderators for heavy drinking. For acamprosate, meta-regression including all of the moderators identified only detoxification before treatment as a significant moderator.

Other results were reported in the review. There was some evidence of publication bias.

Authors' conclusions

Naltrexone should be considered for patients who have a goal of reducing heavy drinking days whereas acamprosate is a better option for those who seek abstinence. Both medications seem to be more effective when participants are detoxified and abstinent when treatment begins.

CRD commentary

The review question and supporting inclusion criteria were broadly defined. The literature search was adequate but was restricted by language and did not appear to include a search for unpublished data, so potentially relevant data may have been missed. All included trials were randomised controlled trials but their quality was unclear as the review did not appear to include a quality assessment. Data extraction was performed in duplicate; it was unclear whether this was also true for study selection so reviewer error and bias could not be ruled out.

There was considerable variation between the trials. The authors attempted to explore factors that caused heterogeneity. It was unclear whether the various data transformations performed by the authors were appropriate. The authors went some way to investigate the effect these transformations may have had on the results. The authors acknowledged the relatively short trial durations and lack of follow-up and the sometimes small number of studies included in analyses.

Given the limitations of the evidence, it is not possible to determine which treatment is most effective under what circumstances. As such, the authors’ conclusions should be treated with caution as they may not be reliable.

Implications of the review for practice and research

Practice: The authors stated that eight people would need to be treated with acamprosate to achieve an additional case of abstinence and nine people would need to be treated with naltrexone to prevent an additional case of return to heavy drinking.

Research: The authors stated that future research was needed to better understand the outcomes for which and the conditions under which pharmacotherapy for alcohol use disorders was most efficacious. Future research could also examine medication adherence and investigate how naltrexone and acamprosate might be usefully integrated with other treatments.

Funding

US National Institute on Alcohol Abuse and Alcoholism, US Department of Veteran Affairs Office of Research and Development, Health Services Research and Development Service and Substance Use Disorder Quality Enhancement Research Initiative.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.